Chronic inflammation is a major characteristic of the typical aging process. The view that the central nervous system is immunologically privileged, however, is challenged by evidence linking low level, chronic inflammation to neurologic injury, neurodegeneration, and cognitive dysfunction. The degree of risk posed by inflammation and the underlying mechanisms of injury remain unclear. The overarching goal of this proposal is to better define the impact of chronic inflammation on brain structure and function. We propose to study four potential downstream effects of chronic inflammation on the brain: 1) Alzheimer's-related changes; 2) white matter injury; 3) network connectivity; and 4) cognition. We will longitudinally study 150 functionally normal community-dwelling subjects over the age of 65 selected from on-going, well-characterized cohorts at UCSF. We will quantify chronic inflammation using several well established markers in serum, plasma, and cerebrospinal fluid. Innovative MRI and PET molecular neuroimaging methods will measure microstructural integrity of white matter tracts, functional connectivity networks, and Alzheimer's-related deposition of brain amyloid. Cerebrospinal fluid (CSF) obtained on a subset of cases will further our understanding of specific inflammatory profiles in the periphery and brain. The cognitive phenotype(s) associated with chronic inflammation will be defined using methods from cognitive neuroscience, and we will explore potential mechanisms by which chronic inflammation interacts with brain structure and function. Results from this project will potentially guide clinial trials and identify elderly subjects with treatable and reversible risks for adverse neurological and cognitive aging.